Preventing immunotherapy-induced edema using angiotensin receptor blockers

Abstract

The disclosure features methods and compositions for the prevention of immunotherapy induced edema in glioblastoma patients undergoing immunotherapy.

1 . A method for treating glioblastoma in a subject, the method comprising administering a therapeutically effective amount of losartan to the subject, thereby treating glioblastoma. 
     
     
         2 . The method of  claim 1 , further comprising administering an antiprogrammed cell death (PD1/PD-L1) therapy. 
     
     
         3 . The method of  claim 2 , wherein the method comprises administering an anti-PD1 antibody or an anti-PD-L1 antibody. 
     
     
         4 . The method of  claims 2 or 3 , wherein losartan in administered prior to antiprogrammed cell death therapy. 
     
     
         5 . The method of  claims 2 or 3 , where in losartan is administered throughout antiprogrammed cell death therapy. 
     
     
         6 . A method for treating cerebral edema in a subject having glioblastoma, the method comprising administering a therapeutically effective amount of losartan to the subject, thereby treating cerebral edema. 
     
     
         7 . The method of  claim 6 , wherein the cerebral edema is an immune checkpoint blocker induced edema. 
     
     
         8 . The method of  claim 7 , wherein the method comprises administering losartan prior to administering an immune checkpoint blocker. 
     
     
         9 . The method of  claim 7 , wherein the method comprises administering losartan concomitantly with the immune checkpoint blocker. 
     
     
         10 . A method for improving vascular function of a glioblastoma in a subject, the method comprising administering a therapeutically effective amount of losartan to the subject, thereby improving vascular function of the glioblastoma. 
     
     
         11 . A method for reprogramming a glioblastoma tumor microenvironment in a subject, the method comprising administering to the subject a therapeutically effective amount of losartan, thereby reprogramming the glioblastoma tumor microenvironment. 
     
     
         12 . The method of  claim 11 , wherein the glioblastoma tumor microenvironment is reprogrammed from immunosuppressive to immunostimulatory. 
     
     
         13 . A method for reducing immunotherapy induced brain edema in a subject in need thereof, the method comprising administering an effective amount of an angiotensin receptor blocker to the subject, thereby reducing immunotherapy induced brain edema in the subject. 
     
     
         14 . The method of  claim 13 , wherein the immunotherapy induced brain edema is an immune checkpoint blocker induced edema. 
     
     
         15 . The method of  claim 14 , wherein the immune checkpoint blocker is an anti-PD1 antibody or an anti-PD-L1 antibody. 
     
     
         16 . The method of  claim 13 or 14 , wherein the brain edema is cerebral edema. 
     
     
         17 . The method of any one of  claims 13-16 , wherein the subject has glioblastoma. 
     
     
         18 . A method for treating glioblastoma in a subject in need thereof, the method comprising administering an effective amount of an angiotensin receptor blocker to the subject in combination with an immune checkpoint blocker, thereby treating the glioblastoma. 
     
     
         19 . The method of any one of  claims 13-18 , wherein the angiotensin receptor blocker comprises losartan, valsartan, olmesartan, telmisartan, azilsartan, medoxomil, irbesartan, candesartan, or eprosartan. 
     
     
         20 . The method of  claim 19 , wherein the angiotensin receptor blocker is losartan. 
     
     
         21 . The method of  claim 19 or 20 , wherein losartan is administered to the subject in combination with an anti-PD1 antibody. 
     
     
         22 . The method of  claim 21 , wherein losartan is administered to the subject in combination with an anti-PD1 antibody and a standard of care treatment. 
     
     
         23 . The method of  claim 22 , wherein the standard of care treatment includes surgical resection, radiation, or temozolomide. 
     
     
         24 . The method of any one of  claims 19-23 , wherein losartan reduces immunotherapy induced brain edema in the subject by reducing the expression of membrane-type matrix metalloproteinases in tumor endothelial cells. 
     
     
         25 . A method for reducing immunotherapy induced brain edema in a subject in need thereof, the method comprising administering an effective amount of a membrane-type matrix metalloproteinase inhibitor to the subject, thereby reducing immunotherapy induced brain edema in the subject. 
     
     
         26 . The method of  claim 25 , wherein the immunotherapy induced brain edema is an immune checkpoint blocker induced edema. 
     
     
         27 . The method of  claim 26 , wherein the immune checkpoint blocker is an anti-PD1 antibody or an anti-PD-L1 antibody. 
     
     
         28 . The method of  claim 25 or 26 , wherein the brain edema is cerebral edema. 
     
     
         29 . The method of any one of  claims 25-28 , wherein the subject has glioblastoma. 
     
     
         30 . A method for treating glioblastoma in a subject in need thereof, the method comprising administering an effective amount of a membrane-type matrix metalloproteinase inhibitor to the subject in combination with an immune checkpoint blocker, thereby treating the glioblastoma. 
     
     
         31 . The method of any one of  claims 24-30 , wherein the membrane-type matrix metalloproteinase inhibitor is Ilomastat. 
     
     
         32 . The method of any one of  claims 24-31 , wherein the membrane-type matrix metalloproteinases are membrane-type matrix metalloproteinase 1 and membrane-type matrix metalloproteinase 2. 
     
     
         33 . The method of any one of  claims 24-32 , wherein the membrane-type matrix metalloproteinases are expressed in tumor endothelial cells. 
     
     
         34 . The method of  claim 31 , wherein Ilomastat is administered to the subject in combination with an anti-PD1 antibody. 
     
     
         35 . The method of  claim 34 , wherein Ilomastat is administered to the subject in combination with an anti-PD1 antibody and a standard of care treatment. 
     
     
         36 . The method of  claim 35 , wherein the standard of care treatment includes surgical resection, radiation, or temozolomide. 
     
     
         37 . The method of any one of  claims 1-36 , wherein the subject is a human. 
     
     
         38 . A method of reducing immunotherapy induced edema in a patient undergoing immunotherapy, the method comprising administering a composition that reduces membrane-type matrix metalloproteinase 1 and membrane-type matrix metalloproteinase 2 activity in endothelial cells in the patient. 
     
     
         39 . The method of  claim 38 , wherein the composition is Ilomastat. 
     
     
         40 . A method of reducing immunotherapy induced edema in a patient undergoing immunotherapy, the methods comprising administering an angiotensin receptor blocker to the patient in an amount effective to reduce the edema. 
     
     
         41 . The method of  claim 40 , wherein the angiotensin receptor blocker comprises losartan, valsartan, olmesartan, telmisartan, azilsartan, medoxomil, irbesartan, candesartan, or eprosartan. 
     
     
         42 . The method of  claims 38-41 , wherein the patient is a human.